Generation and trapping of electron-deficient 1,2-cyclohexadienes. Unexpected hetero-Diels-Alder reactivity

Article abstract of DOI:10.1039/d0ob02285c

Keto-substituted 1,2-cyclohexadienes were generated by base-mediated (KOt-Bu) elimination, and found to dimerize via an unprecedented formal hetero-Diels-Alder process, followed by hydration. These highly reactive cyclic allene intermediates were also tra

Full text of DOI:10.1039/d0ob02285c

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DOI: 10.1039/D0OB02285C
Journal Name
COMMUNICATION
Generation and Trapping of Electron-Deficient 1,2-
Cyclohexadienes. Unexpected Hetero-Diels-Alder Reactivity
†
a,b
a
c
,c
Received 00th January 20xx,
Accepted 00th January 20xx
Baolei Wang, Marius-Georgian Constantin, Simarpreet Singh, Rebecca L. Davis,* and F. G.
West*
,a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Keto-substituted 1,2-cyclohexadienes were generated by base- its 1-acetoxy substituted variant display similar cycloaddition
mediated (KOt-Bu) elimination, and found to dimerize via an behaviour, we set out to study the effect of substitution by
unprecedented formal hetero-Diels-Alder process, followed by electron-withdrawing groups on allene reactivity. Here we
hydration. These highly reactive cyclic allene intermediates were report the ready generation of keto- and cyano-substituted 1,2-
also trapped in Diels-Alder reactions by furan, 2,5-dimethylfuran, cyclohexadienes, their efficient participation as dienophiles in
or diphenylisobenzofuran to afford cycloadducts with high regio- Diels-Alder cycloadditions, and previously unknown
and diastereoselectivity, and could also be intercepted in a hetero- dimerization and enamine capture via apparent hetero-Diels-
Diels-Alder process with enamine dienophiles. Endo/exo Alder cycloaddition.
stereochemistry was unambiguously determined via X-ray
Most recent work in this area has relied upon fluoride-
crystallography in the case of nitrile-substituted 1,2- induced desilylative elimination of alkenyl halides or triflates to
6
,7
cyclohexadiene. DFT calculations indicate that the novel hetero- generate the transient allenes. However, given the acidifying
Diels-Alder processes observed with these allenes occur via a effect of an electron-withdrawing group on the allene
concerted asynchronous cycloaddition mechanism.
precursors, we hoped to employ base-mediated deprotonation,
an approach that would greatly simplify substrate design. In
fact, the first report of 1,2-cyclohexadiene formation and
trapping by Wittig and Fritze involved treatment of
bromocyclohexene with KOt-Bu in an E2 elimination reaction,
and Hioki et al. have shown that alkenyl triflates can also be
Imposition of ring strain is a proven approach towards
enhancing reactivity, and revealing new bond-forming
processes that often occur under mild reaction conditions.
1
Polycyclic scaffolds containing multiple small rings have been
shown to undergo a variety of novel and efficient coupling
reactions with various functional groups, allowing rapid build-
8
used. More recently, Nendel et al. showed that a mixture of 2-
cyclohexene-1-carboxylate esters 1a and isomeric 1-chloro-6-
carboalkoxycyclohexenes 1b underwent elimination to afford
ester-substituted 1,2-cyclohexadienes 2, which were trapped in
the presence of excess furan to provide a mixture of
2
up of molecular complexity. Distorted -systems, such as
those found in arynes or cycloalkynes,4 provide another
3
approach to strain-induced reactivity.
Allenes encased within 8-membered or smaller rings also
experience significant strain, and show corresponding trends
9
regioisomeric Diels-Alder adducts 3 and 4 (Scheme 1).
5
towards enhanced reactivity. Both our group and Garg’s have
previously reported the efficient trapping of 1,2-
cyclohexadienes with 1,3-dienes, 1,3-dipoles, or transition
6
metals. Having observed that the parent cyclohexadiene and
a. Department of Chemistry, University of Alberta, E3-43 Gunning-Lemieux
Chemistry Centre, Edmonton, AB, Canada, T6G 2G2. Tel: +1 780 492-8187; Fax: +1
7
80 492 8231; E-mail: frederick.west@ualberta.ca
b.
State-Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation
Center of Chemical Science and Engineering, College of Chemistry, Nankai
University, Tianjin 300071, P. R. China.
Department of Chemistry, University of Manitoba, 360 Parker Bldg., 144 Dysart
Rd., Winnipeg, MN, Canada, R3T 2N2
Scheme 1 Generation and trapping of ester-substituted 1,2-cyclohexadienes
c.
Four target substrates were identified (Scheme 2). 2-Aroyl
†
Electronic supplementary information (ESI) available: Experimental procedures enol triflates 5a-c could be prepared in two steps from
and spectral data for all new compounds, including the X-ray crystal structures of
2d 13d, and 16a (CCDC 1850686, 1850685, and 2017584). For ESI and
10
morpholinocyclohexene.
2-Cyano enol triflate 5d was
1
prepared via Thorpe-Ziegler cyclization of pimelonitrile
crystallographic data in electronic format see DOI: 10.1039/x0xx00000x.
This journal is © The Royal Society of Chemistry 20xx
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followed by sulfonylation.11 Notably, in all cases only the fully initial elimination of triflate should furnish allene 7a. Hetero-
View Article Online
DOI: 10.1039/D0OB02285C
substituted enol triflate regioisomer was isolated, in contrast to Diels-Alder dimerization could then occur between the enone
9
the alkenyl chlorides described in the previous work.
moiety of one molecule of 7a and the remote C=C bond of the
other to provide cycloadduct 8a. Upon aqueous work-up, 8a
could isomerize to the fully conjugated isomer 9a, and
hydration of this alkylidenepyran during work-up would give the
observed product. Alternatively, nucleophilic attack of 7a by the
conjugate base of 5a at the reactive central carbon would
establish the key C2–C3 connection, and subsequent Michael
addition of the enolate oxygen and elimination of triflate would
§§
intercept tricyclic intermediate 9a. Unsurprisingly, nitrile
substrate 5d, which lacks a carbonyl moiety, did not afford any
pyranol product, though it was efficiently consumed under the
reaction conditions. Regardless of the mechanism, we believe
this mode of dimerization is entirely unprecedented; no such
reactivity was reported for the corresponding ester-substituted
Scheme 2 Preparation of enol triflates 5a-d
Conditions for elimination of the enol triflate 5a were then
explored. Weaker bases (Et N, DBU, NaOH, KOH) effected little
3
or no conversion, or resulted in complex product mixtures that
included the diketone hydrolysis product from enol triflate
cleavage. KOt-Bu in various solvents and stoichiometries and at
9
allenes.
‡
temperatures ranging from –78 to 120 °C was found to consume
5
a, producing varying amounts of a new product corresponding
to an apparent allene dimer + H O (Table 1). The most
2
favourable conditions were found to be KOt-Bu (1.2 equiv) in
THF at rt, which afforded the “hydrated dimer” in 26% yield.
This product, 6a, was shown via HMBC analysis to be a tricyclic
pyranol. Notably, formation of 6a does not involve a [2+2]
dimerization, which is the usual background process that
§
complicates trapping chemistry of cyclic allenes. The
corresponding pyranols 6b and 6c could be obtained from 5b,c
in modest yields under these conditions.
Table 1 Base-mediated elimination reactions of 5a-da
Scheme 3 Possible mechanisms for the formation of 6a
The mechanism of dimerization was examined via DFT
calculations employing the M062x/6-31+G(d,p) functional with
Entry Substrate Solvent Equiv KOt-Bu Temp
Time
1.5 h
12 h
40 min
2 h
Yield 6 (%)b
1
2,13,14
IEFPCM solvent model (THF).
Our model indicates that the
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5a
5a
5b
5c
5d
THF
THF
THF
THF
THF
THF
THF
THF
THF
1.02
1.75
2.1
4.0
1.2
1.2
1.2
1.2
1.2
rt
rt
rt
rt
rt
rt
rt
rt
rt
6c
5
[
4+2] cycloaddition occurs in a concerted asynchronous manner
with the carbon-carbon bond forming earlier than the carbon-
oxygen bond (2.20 Å vs 2.90 Å, respectively, in the transition
state structure). Despite the asynchronicity of the transition
state structure, intrinsic reaction coordinate (IRC) calculations
indicate that this transition state leads directly to reactants and
products. This reaction occurs with a barrier of 17.7 kcal/mol
and the resulting [4+2] adduct is favoured by 90.5 kcal/mol,
relative to the starting allenes (Figure 1a).
c
8
d
--
c
c
3h
20
26
11
12 h
12 h
12 h
12 h
e
42c
--d
aGeneral conditions: substrate 5 and base were dissolved in anhydrous solvent and
stirred under nitrogen atmosphere at the indicated temperature for the indicated
Studies on the nucleophilic attack of 7a by the conjugate
time. Yields given are for isolated product 6 after purification. An additional 5- base of 5a show that it proceeds with a barrier of 20.1 kcal/mol
b
c
1
0% recovered starting material was isolated. dAlthough most or all of 5 was
and results in the formation of an intermediate that is favoured
by 34.8 kcal/mol, relative to the combined energies of 7a and
conjugate base of 5a (Figure 1b). These results suggest that
either addition pathway is plausible under the given reaction
conditions and would likely be dependent on the lifetime of the
e
consumed, no clean product could be isolated. An additional 27% recovered
starting material was isolated.
The unusual connectivity of 6a-c suggests a possible hetero-
Diels-Alder dimerization pathway involving two molecules of
cyclic allene (Scheme 3). As shown for the specific case of 6a,
1
5
anionic intermediate and rate of formation of the allene.
2
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a) Concerted Cycloaddition
yields. Nitrile-substituted enol triflate 5d also reacted with 2,5-
dimethylfuran to provide 11d, albeit in modest yield (20%).
Notably, exclusive reaction at the allene C=C bond proximal
to (and conjugated with) the ketone or nitrile moieties was
View Article Online
DOI: 10.1039/D0OB02285C
Ph
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
observed, in contrast to the ester examples, which furnished a
9
2
-3:1 mixture of regioisomers. In the case of 5a-c, this may be
[
0.0]
+17.7
-90.5
attributed to the greater degree of dienophile activation by the
more electron-withdrawing keto groups. In addition to the high
regioselectivity, complete diastereoselectivity in favour of the
endo cycloadducts was also seen. Assignment of endo relative
configuration was supported by the characteristic upfield shift
b) Anion Addition
Ph
Ph
Ph
O
OTf
Ph
O
O
-
OTf
O
OTf
O
-
Ph
Ph
O
16
seen for one of the cyclohexene protons, as well as TROESY
correlations between dihydrofuran alkene protons and the
[
0.0]
+20.1
-34.8
Figure 1 DFT investigation of the (a) concerted allene dimerization and (b) stepwise same upfield proton (Figure 2), neither of which would be
anionic addition pathways leading to formation of 6a. Reported values are Gibbs Free
energies and are reported in kcal/mol.
observed for exo cycloadducts. Furthermore, correlation with
NMR data for DPIBF adducts 12d and 13d (vide infra), for which
unequivocal assignment was possible via X-ray diffraction
analysis, provided additional support for this assignment.
Although near complete consumption of 5a-c was achieved
under these conditions, only relatively low yields of 6 could be
obtained, reflecting the multitude of pathways available to the
intermediate cyclic allenes (7). We therefore examined
alternative reactivity through the use of external 1,3-diene
9
traps, beginning with furan (Table 2). As in the previous cases,
large amounts of furan were required for effective Diels-Alder
trapping of the allene derived from 5a in preference to
dimerization or uncharacterized decomposition pathways.
1
Figure 2 Characteristic H NMR features of endo furan cycloadducts
Treatment of the enol triflate (5) with 2 equivalents KOt-Bu in
equal volumes of furan and THF (137 equivalents of furan)
Use of the highly reactive Diels-Alder diene 1,3-
furnished cycloadduct 10a in 50% yield. Substrates 5b-d
diphenylisobenzofuran (DPIBF) to trap allenes 7a-d obviated
afforded the corresponding cycloadducts 10b-d in 45–82%
the need for large excesses of the diene. As in the case of furan
Table 2 Diels-Alder trapping of cyclic allenes derived from 5a-da
trapping, keto-substituted allenes provided cycloadducts 12a-c
with complete regio- and stereoselectivity. However, nitrile
case 5d afforded both endo 12d and exo 13d in a 3:1 ratio.
Rigorous structural assignment for both isomers was obtained
via X-ray crystallographic analysis.
To explore the nature of the mechanism and to understand
the observed regio- and diastereoselectivities of the trapping
reactions, DFT calculations were performed on the Diels–Alder
reactions of allenes formed from substrates 5a and 5d (7a and
7
d, respectively) with furan, 2,5-dimethyl furan, and DPIBF.
Entry Substrate
Trap (equiv)
Product(s) (yield %)b
Herein, we present the results of the computations performed
on allene 7d with furan. The calculations on all other allenes and
dienes followed similar energetic trends and can be found in the
Electronic Supplementary Information.
Examination of the cycloaddition occurring across the 1,2
bond of 7d reveals that both the endo and exo additions (TS1
and TS2, respectively) proceed in a concerted, asynchronous
fashion, with the transition state structure for the endo addition
favoured by 2.1 kcal/mol (Figure 3a). The formation of the endo
adduct is exergonic by 38.9 kcal/mol, and is thermodynamically
favoured over the formation of the exo product by 1.0 kcal/mol.
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5d
5a
5b
5c
5c
5d
furan (137)
furan (137)
furan (137)
furan (92) d
10a (50)c
10b (82) c
10c (60) c
10d (45)
d
e
2,5-dimethylfuran (65)
11d (20)
f
g
DPIBF (2)
12a (20) + 6a (5)
12b (23)g
f
DPIBF (2)
f
12c (29) + 6c (8)g
12c (36)h
DPIBF (2)
f
DPIBF (10)
f
d
1
0
DPIBF (3)
12d (36) + 13d (12)
a
General conditions: substrate 5, trap, and KOt-Bu (2 equiv) were dissolved in THF
b
and stirred at rt under nitrogen atmosphere for 2 h. Yields given are for isolated The energetic favourability of endo addition (TS1) over exo
c
products 10–13 after purification. An additional 2-5% recovered starting material
addition (TS2) can be justified by secondary orbital interactions
between the lone pair on the furan oxygen and the electron
withdrawing group at C1 of the allene. Noncovalent interaction
d
e
was isolated. In the case of nitrile 5d, reactions were completed in 30-45 min. An
f
additional 10% recovered starting material was isolated. DPIBF
diphenylisobenzofuran. In trapping reactions using DPIBF, 5a (33%), 5b (7%) and
= 1,3-
g
h
5
c (12%) were also recovered. 5c (19%) was recovered.
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(
NCI) analysis on TS1 and TS2 confirmed larger, favourable observations and with previous reports on electron deficient
View Article Online
DOI: 10.1039/D0OB02285C
electrostatic interactions in TS1 (where the O of the furan is
allenes undergoing preferential cycloaddition proximal to the
6
,9
EWG.
Given the proposed hetero-Diels-Alder dimerization
mechanism for the formation of 6a-c, we wondered if cyclic
allenes 7a-b could react as heterodienes in a crossed [4+2]-
1
7
cycloaddition with a suitable olefinic trap. Since this process is
presumed to occur via inverse electron-demand, we reasoned
that electron-rich trapping reagents should be favoured, and
examined several enol ethers and enamines (Table 3). While no
evidence of reaction with enol ethers 14a,b was seen, enamines
1
5a-e furnished dihydropyran aminals 16a-g as single isomers
in modest yields. Although these products were anticipated to
be hydrolytically sensitive, their purification by normal-phase
chromatography was tolerated with little decomposition.
Importantly, cycloadduct 16a is crystalline, and we were able to
confirm its structure by single crystal X-ray diffraction analysis.
Acyclic enamine 15c furnished cycloadducts 16c and 16g as
single diastereomers, consistent with a concerted, pericyclic
process rather than an alternative stepwise mechanism
involving initial Michael addition of the enamine to the allene
central carbon atom. The morpholine enamine of
cyclooctenone (15f) did not furnish any cycloadduct products,
perhaps a consequence of reduced reactivity due to steric clash
between the heterodiene and transannular methylene protons
in the 8-membered enamine. Enaminone 15g afforded adduct
1
6h in low yield, presumably a consequence of its reduced
electron availability. Notably, this product, a dendralene
embedded within a tricyclic scaffold, lacked the morpholine
moiety. This is likely due to its elimination under the basic
conditions, given the enhanced acidity afforded by the
cyclohexanone carbonyl group.
As in the dimerization process shown in Scheme 3, the
formation of cycloadducts 16 could conceivably arise by either
a pericyclic Diels-Alder process, or via stepwise ionic addition of
the nucleophilic enamines to the electron-deficient allenes.
Retention of stereochemical information in the two cases
Figure 3 a) Optimized transition state structures leading to the possible diastereomers
and regioisomers for the addition of furan with allene 7d. Bond lengths are given in
Ångstroms. b) NCI plot (isovalue of 0.40) of TS1 and TS2. (Blue = strongly attractive
interactions, Green
= weakly attractive interactions, Red = strongly repulsive
interactions) c) Orbital coefficients (left) and depiction of the LUMO (right) of allene 7d. involving acyclic enamine 15c offers evidence for a concerted
mechanism. DFT calculations on the cycloaddition of allene 7a
with enamine 15a indicate that the [4+2] cycloaddition occurs
in a concerted asynchronous manner, with the carbon-carbon
bond forming earlier than the carbon-oxygen bond (2.57 and
interacting with the cyano group) as compared to TS2 (where
the C3/C4 2-carbon unit of the furan is interacting with the
cyano group).
3
.12 Å, respectively) (Figure 4). The cycloaddition occurs with a
In contrast to the cycloaddition occurring across the 1,2
bond of 7d, the addition across the 2,3 bond of 7d occurs via a
stepwise mechanism with the bond between C2 of the allene
and the furan forming first. The transition state structures for
the first addition step for both the endo (TS3) and exo (TS4)
approaches of the allene are nearly equal in energy, with the
exo addition being lower in energy by 0.4 kcal/mol (Figure 3b).
The stepwise nature of the addition across the 2,3-bond is likely
the result of poor orbital overlap with between the furan and
the orbital at C3 of the allene. In the LUMO of 7d, the orbital
coefficient on C3 is smaller than that of C1 or C2 (Figure 3c).
Comparison of all four transition state structures (TS1, TS2,
TS3, TS4) shows the endo addition of furan across the C1=C2
bond of the allene to be favoured by ~3 kcal/mol over all other
approaches. This is consistent with the experimental
1
8
barrier of 12.4 kcal/mol and is exergonic by 52.4 kcal/mol. As
shown in Figure 4, the cycloaddition occurs through a transition
state structure (TS5) that places the N of the enamine directly
Figure 4 a) Optimized transition state structure for the favoured diastereomer of the
cycloaddition of 5a with 15a. b) NCI plot of TS5.
4
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Table 3 Hetero-Diels-Alder trapping of cyclic allenes derived from 5a,b with electron-rich over the C of the carbonyl on the allene. This allows for
View Article Online
heterodienophilesa
DOI: 10.1039/D0OB02285C
favourable secondary orbital interactions, as indicated by the
1
9
NCI plot of TS5 (Figure 4b). The concerted nature of this
reaction is consistent with the mechanism calculated for the
dimerization of 5a and with the observed stereochemistry of
1
6c and 16g.
We have described the reactions of four new examples of
Entry Substrate
Trap
Product (yield %)b
cyclic allenes bearing electron-withdrawing substituents, and
their generation from readily available enol triflate precursors.
Ketoallenes 7a-c undergo a novel dimerization process involving
an apparent hetero-Diels-Alder cycloaddition, and this has been
extended to intermolecular trapping with enamines. Successful
trapping was also possible with dienes furan, 2,5-dimethylfuran,
and DPIBF, and in all cases proceeded with complete
regioselectivity for the more electron-deficient allene  bond.
Furthermore, in all but one case complete diastereoselectivity
in favour of the endo diastereomer was seen. DFT calculations
support an asynchronous concerted mechanism for heteor-
Diels-Alder cycloadditions, and offer a possible explanation for
the observed high endo selectivity. Further reactivity of this
class of highly reactive cyclic allenes is under current
investigation and will be described elsewhere.
--c
1
5a
--c
2
5a
3
4
5a
5a
(65)
(24)
(
29)
5
5a
Acknowledgment is made to the donors of the American
Chemical Society Petroleum Research Fund for support of this
research. We also thank the Natural Science and Engineering
Research Council of Canada (NSERC) for partial support, and
China Scholarship Council for a Visiting Professorship (BW). RD
and SS would like to thank the Natural Science and Engineering
Research Council of Canada (NSERC) and Compute Canada for
support.
6
7
8
9
5a
5b
5a
5b
(
9)
(46)
Conflicts of interest
There are no conflicts to declare.
(
51)
Notes and references
‡
§
See ESI for a complete list of basic conditions examined with 5a.
Although the cyclobutane [2+2] dimer could not be isolated,
(19)
mass spectral analysis of the crude reaction mixture indicated the
presence of a nonhydrated dimer, suggesting that its formation in
small quantities cannot be ruled out.
§§ The alternative ionic mechanistic pathway does not require
two molecules of transient allene to encounter and react with
each other. However, the known [2+2] dimerization mode of
allenes indicates that such processes can be efficient. We thank
an anonymous referee for this suggestion.
1
0
1
5a
5a
--c
Ph
1
A. Nikolaev and A. Orellana, Synthesis, 2016, 48, 1741; P.
Chen and G. Dong, Chem. Eur. J., 2016, 22, 18290; G.
Fumagalli, S. Stanton and J. F. Bower, Chem. Rev., 2017, 117,
1
N
O
(6)
O
O
1
5g
9
404.
M. A. A. Walczak, T. Krainz and P. Wipf, Acc. Chem. Res.,
015, 48, 1149; R. Gianatassio, J. M. Lopchuk, J. Wang, C.-M.
O
2
1
6h
2
aGeneral conditions: KOt-Bu (1.5 equiv) in THF (0.3 M) was added dropwise over
.5 h to a solution of substrate 5 in THF (0.1 M) and olefin trap (10 equiv) at rt.
Reactions were stirred under nitrogen atmosphere for 3 h. Yields given are for
isolated products 16a-g after purification. Triflate 5a was fully consumed, but no
adducts derived from allene intermediate 7a and enol ethers 14 or enamine 15f
could be isolated from the complex reaction mixture.
Pan, L. R. Malins, L. Prieto, T. A. Brandt, M. R. Collins, G. M.
Gallego, N. W. Sach, J. E. Spangler, H. Zhu and P. S. Baran,
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2016, 49, 1658; O. J. Diamond and T. B. Marder, Org. Chem.
0
b
c
3
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